A substantial body of evidence indicates that peripheral opioid peptides and their receptors have a major physiological role in the regulation of gut motility. Consequently gastrointestinal disorders such as idiopathic constipation and irritable bowel syndrome may relate to a dysfunction of opioid receptor mediated control and agents which act as antagonists for these receptors may benefit a patient suffering from such a dysfunction.
Natural and synthetic opiates such as morphine have been used extensively in the mediation of pain. However, these agents can produce undesirable side effects such as constipation, nausea, and vomiting which are peripheral to the desired action as analgesics. Thus, a peripheral opioid antagonist should not substantially affect the analgesic effects of the opiate while acting to control gastrointestinal function and to minimize the undesirable side effects of the narcotic drug.
A number of opioid antagonists have been reported including naloxone and naltrexone (Blumberg et al., Toxicol. Appl. Pharmacol., 10, 406, 1967). Other derivatives of these compounds have been recently reported (Portoghese et al., J. Med. Chem., 31, 281-282, 1988). 4-Arylpiperidines have also been reported as having analgesic activity and in some instances acting as narcotic antagonists. Zimmerman, U.S. Pat. No. 4,191,771 (1980); Barnett, U.S. Pat. No. 4,581,456 (1986): Zimmerman, U.S. Pat. No. 4,081,450 (1978). These compounds are disclosed as having useful analgesic activity and in some cases acting as potent narcotic antagonists.
It would be advantageous to have compounds which would act as antagonists to the peripheral effects of opiate analgesics and endogenous opioid peptides. It would also be advantageous if these compounds had a minimal effect on the analgesic activity of the opiate drugs. It would be further advantageous to have compounds which can act to minimize the effects of idiopathic constipation and irritable bowel syndrome.
It has now been found that the N-substituted piperidines of the instant invention are useful as peripherally selective opioid antagonists. The instant compounds are useful in preventing peripherally mediated, undersired opiate effects and in relieving the symptoms of idiopathic constipation and irritable bowel syndrome. Certain of the instant compounds are also useful as intermediates in preparing new piperidine compounds.